Infection with hepatitis C virus (HCV) and HIV frequently complicate stimulant use in the United States. Our preliminary data implicate stimulants and both viruses as causes of neurocognitive impairment. Distinguishing the causes of impairment is essential for medical diagnosis and therapy of all these conditions. In particular, impairment may interfere with abstinence and medical adherence in recovering drug users. For these reasons, we plan to study the effects of drug use, HCV, and HIV on neuropsychological performance, cerebral metabolites, and immune activation. We recently screened subjects enrolled in our NIDA-sponsored Program Project "NeuroAIDS: Effects of Methamphetamine" for evidence of HCV infection. This preliminary study demonstrated that individuals who were infected with HCV were more neurocognitively impaired than those who were not. In particular, those with HCV-HIV co-infection performed the worst. However, the analysis could not distinguish whether these impairments were attributable to HCV infection or drug use because of sample limitations. The proposed study will be our first step in making this distinction. The primary objectives of the study are 1) to distinguish the effects of drug use, HCV infection, and HIV infection on neuropsychological performance, cerebral metabolism, and immune activation and 2) to evaluate the cerebral metabolic, viral, and other biological correlates of neurocognitive impairment in HCV-infected study participants. We propose a cross-sectional study of 192 participants, stratified in a factorial design by HCV infection, HIV infection, and drug use. We hypothesize that cognitive performance will incrementally worsen based on the number of these risk factors present. Through modeling, we will estimate the individual contribution of each of these conditions. This multidisciplinary study will use four primary assessments: standardized neuropsychological testing, magnetic resonance spectroscopy, markers of HCV and HIV disease activity, and markers of immune activation in plasma and cerebrospinal fluid. The HIV Neurobehavioral Research Center, a Center to Support Programs in AIDS Research, will provide scientific and operational support for this project. Using this approach, we will define the neurocognitive complications in drug users attributable to stimulant use, HCV, and HIV, as well as investigate their mechanisms. The findings of this research will be used to evaluate the feasibility of an interventional study, and to assist in its design.